The present invention relates to novel polymyxin, circulin and octapeptin derivatives and pharmaceutically acceptable salts thereof and their use in therapy to sensitize Gram-negative bacteria to antibacterial agents and/or to the host (human, animal) defence mechanism complement. The present invention also relates to a method of sensitizing Gram-negative bacteria to antibacterial agents and to host defence mechanism complement and to a pharmaceutical composition for use in this method. Finally the present invention relates to a method of producing a polymyxin B nonapeptide which also is a novel compound.
One reason for the resistance of bacteria to antibiotics is their cell wall which inhibit the free permeation of antibiotics to their targets inside the cell. Especially evident this is in Gram-negative bacteria which have a unique structure as their outermost barrier to external noxious agents. This special structure is an additional membrane located outside the peptidoglycan and called the outer membrane (OM). The OM of Gram-negative enteric bacteria and Pseudomonas act as an absolute permeability barrier to many antibiotics (e.g. erythromycin, lincomycin, clindamycin, novobiocin, cloxacillin, nafcillin and fusidic acid). The penetration of several other antibiotics (especially penicillin, ampicillin, carbenicillin and most cephalosporins) is also greatly reduced by the OM.
In addition to the antibiotics, the defence mechanisms of the host, such as complement, often synergistic with antibodies, and phagocytosis play a significant role in the inhibition of invading micro-organisms. Unfortunately, Gram-negative bacteria isolated from severe infections, e.g. septicemia, usually show a uniform resistance to complement. They are also poorly phagocytosed, partly because of the mentioned resistance to complement. Interestingly, also the resistance to complement has been attributed to the outer membrane.
Thus, the outer membrane is responsible not only for the resistance of Gram-negative bacteria to many antibiotics, but also for their resistance to the major host defence mechanism complement. Concomitantly, if one could affect the outer membrane structure so that it either loses its function as a permeability barrier to antibiotics or loses its resistance to complement, infections caused by Gram-negative bacteria would be much easier to control. The object of the present invention is to provide a method to affect the outer membrane structure in such a way.